[go: up one dir, main page]

FR2520364A1 - Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants - Google Patents

Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants Download PDF

Info

Publication number
FR2520364A1
FR2520364A1 FR8201348A FR8201348A FR2520364A1 FR 2520364 A1 FR2520364 A1 FR 2520364A1 FR 8201348 A FR8201348 A FR 8201348A FR 8201348 A FR8201348 A FR 8201348A FR 2520364 A1 FR2520364 A1 FR 2520364A1
Authority
FR
France
Prior art keywords
formula
lithium
acid
aggression
phosphoric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
FR8201348A
Other languages
French (fr)
Other versions
FR2520364B1 (en
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to FR8201348A priority Critical patent/FR2520364A1/en
Publication of FR2520364A1 publication Critical patent/FR2520364A1/en
Application granted granted Critical
Publication of FR2520364B1 publication Critical patent/FR2520364B1/fr
Granted legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/28Phosphorus compounds with one or more P—C bonds
    • C07F9/38Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3886Acids containing the structure -C(=X)-P(=X)(XH)2 or NC-P(=X)(XH)2, (X = O, S, Se)
    • C07F9/3891Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Lithium salts of formula R-NH-CO-P(=O)-(OLi)2 (I) and their pharmaceutically-acceptable salts are new (where R is opt. branched alkyl, esp. CH3). (I) is prepd. by treating a phosphoric acid having two acid gps. blocked with an alkyl isocyanate. Blocking of the acid gps. is pref. effected using triethylamine or a basic Li deriv. LD50 of (I: R= CH3)= 3200 mg/kg (route not stated). (I) may be given orally or by injection at a unit dose of 250-750 mg. (I) have a similar effect to Li carbonate, but with a slightly superior action. They therefore cause a decrease in aggression, decrease in movement and curiosity and protection against convulsions.

Description

Médicament, utilisable notamment en psychatrie, ut lisant comme principe actif un N-alkyl carba;noylphosphate de lithiun.Medicinal product, usable in particular in psychatria, using as active ingredient an N-alkyl carba; lithium nucleus phosphate.

La presente Invention concerte un nouveau médicament utilisable notamment en psychiatrie. The present invention relates to a new drug usable in particular in psychiatry.

Le médicament selon l'invention est caractérisé en ce qu'il comporte un produit de formule

Figure img00010001

dans laquelle R est un radical alkyle linéaire ou ramifié et plus particulièrement un radical alkyle inférieur ayant 1 9 4 atomes de carbone, ou un sel pharmaceutiquement acceptable dudit produit de formule (I).The medicament according to the invention is characterized in that it comprises a product of formula
Figure img00010001

wherein R is a linear or branched alkyl radical and more particularly a lower alkyl radical having 1 9 4 carbon atoms, or a pharmaceutically acceptable salt of said product of formula (I).

Parmi les produits de formule (I), spécialement inté ressuant on mentionnera le composé dans lequel R est CH3.  Among the products of formula (I), especially interesting, mention will be made of the compound in which R is CH3.

L'invention concerne également un procédé de préparation des produits de formule I, ce procédé étant caractérisé en ce qu on fait réagir un isocyanate d alkyle sur un acide phosphorique Po H dont deux fonctions acides ont été bloquées. Pour réaliser le blocage de ces deux fonctions acides on peut
- soit réaliser le sel de triéthylamine de l'acide phosphorique que l'on fera réagir avec l'isocyanate
- soit utiliser directement le phosphate dilithique que l'on fait également réagir avec l'isocyanate.
The invention also relates to a process for the preparation of products of formula I, this process being characterized in that an alkyl isocyanate is reacted with a phosphoric acid Po H of which two acid functions have been blocked. To block these two acid functions, we can
- or make the triethylamine salt of phosphoric acid which will be reacted with the isocyanate
- Either directly use the dilithic phosphate which is also reacted with the isocyanate.

L'invention concerne enfin les médicaments qui contiennent au moins un produit de formule (I). I1 a été trouvé en effet que les produits de formule (I) avaient une toxicité faible (la DL50 pour la souris et pour le produit de formule I dans lequel R est CH3 étant environ 3 200 mg/kg par voie ) et une activite pharmacologique qui peut s'exprimer comme suit
- diminution et/ou blocage des systèmes dopaminergiques,
- augmentation, au moins transitoire, de la synthèse de la sérotonine,
- pouvoir analgésique, les conséquences de ces actions se retrouvant dans les constatations suivantes
- diminution de l'agressivité,
- diminution de la motilité et de la curiosité,
- protection contre les convulsions.
Finally, the invention relates to medicaments which contain at least one product of formula (I). I1 was indeed found that the products of formula (I) had a low toxicity (the LD50 for the mouse and for the product of formula I in which R is CH3 being approximately 3,200 mg / kg per route) and a pharmacological activity which can be expressed as follows
- decrease and / or blockage of dopaminergic systems,
- at least transient increase in the synthesis of serotonin,
- analgesic power, the consequences of these actions are found in the following observations
- decrease in aggressiveness,
- decreased motility and curiosity,
- protection against convulsions.

On voit que les produits de formule I ont une activité
de même type que celle du carbonate de lithium mais avec une intensité
nettement supérieure.
We see that the products of formula I have an activity
of the same type as that of lithium carbonate but with an intensity
significantly superior.

Les exemples non limitatifs ci-après illustrent l'in
vention.
The nonlimiting examples below illustrate the in
vention.

Exemple 1
Préparation du N-méthyl-carbamoylphosphate de lithium.
Example 1
Preparation of lithium N-methyl-carbamoylphosphate.

On dissout 0,1 mole d'acide phosphorique cristallisé
dans 30 ml d'acétonitrile anhydre et on y ajoute 0,1 mole de triéthyl
amine anhydre tout en refroidissant le mélange avec de la glace.
0.1 mol of crystalline phosphoric acid is dissolved
in 30 ml of anhydrous acetonitrile and 0.1 mol of triethyl is added thereto
anhydrous amine while cooling the mixture with ice.

On ajoute ensuite progressivement au mélange 0,1 mole
d'isocyanate de méthyle.
0.1 mol is then added gradually to the mixture.
methyl isocyanate.

On laisse revenir à température ambiante et on agite
pendant 12 heures, le pH étant maintenu à 6 par addition de triéthyl
amine:
On concentre sous vide, reprend le produit sec par
200 ml d'eau et on neutralise la solution par adjonction de carbonate
de lithium et d'hydroxyde de lithium jusqu'a virage de la phénol
phtaléine.
Leave to return to room temperature and stir
for 12 hours, the pH being maintained at 6 by addition of triethyl
amine:
Concentrate under vacuum, take up the dry product with
200 ml of water and the solution is neutralized by adding carbonate
lithium and lithium hydroxide until the phenol changes
phthalein.

Les sels de lithium insolubles sont filtrés et la solu
tion est concentrée jusqu'3 obtention d'un produit pulvérulent.
The insoluble lithium salts are filtered and the solu
tion is concentrated until a powdery product is obtained.

On purifie par dissolution (et filtration éventuelle)
dans de l'eau distillée et on précipite la solution obtenue par addi
tion d'alcool éthylique absolu. On filtre et on sèche.
It is purified by dissolution (and optional filtration)
in distilled water and the solution obtained is precipitated by addi
tion of absolute ethyl alcohol. It is filtered and dried.

On obtient un produit se présentant sous forme d'une
poudre blanche dont le spectre NMR montre lvexistence d'un doublet centré à 2,55 ppm (TMS) attribuable à NH-CH3 et dont le spectre IR
montre une bande principale à 1750 cm (carbamate).
A product is obtained in the form of a
white powder whose NMR spectrum shows the existence of a doublet centered at 2.55 ppm (TMS) attributable to NH-CH3 and whose IR spectrum
shows a main band at 1750 cm (carbamate).

Exemple 2
On a préparé le N-méthyl-carbamoylphosphate de lithium
en réalisant tout d'abord la neutralisation partielle de l'acide phos
phorique avec le carbonate (ou l'hydroxyde de lithium) puis on a fait
reagir sur le produit obtenu, dans un solvant inerte, l'isocyanate de
méthyle.
Example 2
We prepared lithium N-methyl-carbamoylphosphate
first of all by partially neutralizing phos acid
phoric with carbonate (or lithium hydroxide) then we did
react on the product obtained, in an inert solvent, the isocyanate of
methyl.

Les propriétés du N-méthyl-carbamoylphosphate de lithium de formule (I) ont été démontrées par les tests suivants réalisés sur des souris et/ou des chiens,
- test concernant l'agressivité induite par des chocs électriques:
dose active 10 MEq par kilo
- test montrant l'activité du produit sur des convulsions produites par un électrochoc
protection de 40% des sujets pour une dose de
5 NEq par kilo
- activité analgésique comparée (test plaque chaude)
avec une dose de 13 hEq par kilo on assure une protec
tion de 42% pour le produit selon l'invention (et de
27% pour le carbonate de lithium)
- test évaluant le blocage des systèmes dopaminergines
- dose active à 100 / 6,75 ISiEq par kilo
- pour le carbonate de lithium on arrive à une dose
active à 50% en utilisant 10,115 '!Eq par kilo
- test sur la sécrétion de sérotonine
- dose active après 24 heures 6,75 iEq par kilo
- pour le carbonate de lithium la dose correspondante
(après 24 heures) serait de 10 hEq par kilo
- test de motilité
- à une dose de 13,5 MEq par kilo, la motilité baisse
de 36%
- pour le carbonate de lithium, à une dose correspondante,
la motilité baisse de 12%.
The properties of lithium N-methyl-carbamoylphosphate of formula (I) have been demonstrated by the following tests carried out on mice and / or dogs,
- test concerning the aggressiveness induced by electric shocks:
active dose 10 MEq per kilo
- test showing the activity of the product on convulsions produced by an electric shock
protection of 40% of subjects for a dose of
5 NEq per kilo
- comparative analgesic activity (hot plate test)
with a dose of 13 hEq per kilo we provide protection
42% for the product according to the invention (and
27% for lithium carbonate)
- test evaluating the blockage of dopaminergin systems
- active dose at 100 / 6.75 ISiEq per kilo
- for lithium carbonate we arrive at a dose
active at 50% using 10,115 '! Eq per kilo
- test on the secretion of serotonin
- active dose after 24 hours 6.75 iEq per kilo
- for lithium carbonate the corresponding dose
(after 24 hours) would be 10 hEq per kilo
- motility test
- at a dose of 13.5 MEq per kilo, motility decreases
36%
- for lithium carbonate, at a corresponding dose,
motility drops by 12%.

Ces résultats montrent l'activité certaine des produits de fprmule I et notamment du dérivé de formule (I) dans lequel R est
CH3.
These results show the certain activity of the products of formula I and in particular of the derivative of formula (I) in which R is
CH3.

Les médicaments contenant un produit de formule (I) (qui peut éventuellement être utilisé en association avec d'autres produits actifs) sont utilisables notamment en psychiatrie pour le traitement des états maniaco-dépressifs. Medicines containing a product of formula (I) (which can optionally be used in combination with other active products) can be used in particular in psychiatry for the treatment of manic-depressive states.

Ces médicaments sont conditionnés pour être administrés sous forme orale (comprimes, dragés, gélules, sirops), sous forme injectable et contiennent par unité de médication de 250 à 750 mg de produit actif.  These drugs are conditioned to be administered in oral form (tablets, dragees, capsules, syrups), in injectable form and contain per unit of medication from 250 to 750 mg of active product.

Claims (6)

REVENDICATIONS 1 - Produits nouveaux, utilisables dans les mddica- ments, caractérisés en ce qu'ils répondent A la formule  1 - New products, usable in medicines, characterized in that they correspond to the formula
Figure img00040001
Figure img00040001
dans laquelle R est un radical alkyle linéaire ou ramifié, et les sels pharmaceutiquement acceptables des produitsde. formule (I). in which R is a linear or branched alkyl radical, and the pharmaceutically acceptable salts of the products. formula (I).
2 - Produit selon la revendication 1, caractérisé en ce que R est CH3 2 - Product according to claim 1, characterized in that R is CH3 3 - Procéde de préparation des produits de formule (I), caractérisé en ce que l'on fait réagir un isocyanate d'alkyle 3 - Process for the preparation of products of formula (I), characterized in that an alkyl isocyanate is reacted sur l'acide phosphorique F04H3 dont deux des fonce: tions acides ont été bloquées. on phosphoric acid F04H3, two of whose acid functions have been blocked. 4 - Procédé selon la revendication 3, caractérisé en ce que le blocage de deux fonctions acides de 11 acide phosphorique a été réalisé avec la triéthylamine. 4 - Process according to claim 3, characterized in that the blocking of two acid functions of 11 phosphoric acid was carried out with triethylamine. 5 - Procédé selon la revendication 3, caractérisé en ce que le blocage de deux fonctions acides de l'acide phosphorique a été réalisé par réaction de l'acide avec un dérivé basique du lithium. 5 - Process according to claim 3, characterized in that the blocking of two acid functions of phosphoric acid was carried out by reaction of the acid with a basic derivative of lithium. 6 - Médicaments utilisables notamment en psychiatrie, caractérisés en ce outils contiennent au moins un produit selon la revendication 1.  6 - Medicines which can be used in particular in psychiatry, characterized in this tool, contain at least one product according to claim 1.
FR8201348A 1982-01-28 1982-01-28 Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants Granted FR2520364A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FR8201348A FR2520364A1 (en) 1982-01-28 1982-01-28 Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8201348A FR2520364A1 (en) 1982-01-28 1982-01-28 Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants

Publications (2)

Publication Number Publication Date
FR2520364A1 true FR2520364A1 (en) 1983-07-29
FR2520364B1 FR2520364B1 (en) 1984-05-04

Family

ID=9270414

Family Applications (1)

Application Number Title Priority Date Filing Date
FR8201348A Granted FR2520364A1 (en) 1982-01-28 1982-01-28 Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants

Country Status (1)

Country Link
FR (1) FR2520364A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129628A1 (en) * 1983-06-23 1985-01-02 Marcel Richard Medicine, especially useful in psychiatry, which uses as the active constituent a lithium N-alkylcarbamoyl phosphate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4063923A (en) * 1973-07-23 1977-12-20 E. I. Du Pont De Nemours And Company Carbamoylphosphonic acid brush control agents
EP0021391A1 (en) * 1979-07-03 1981-01-07 Bayer Ag Phosphonoformic acid hydrazides, process for their preparation and their use as medicines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4063923A (en) * 1973-07-23 1977-12-20 E. I. Du Pont De Nemours And Company Carbamoylphosphonic acid brush control agents
EP0021391A1 (en) * 1979-07-03 1981-01-07 Bayer Ag Phosphonoformic acid hydrazides, process for their preparation and their use as medicines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EXBK/69 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129628A1 (en) * 1983-06-23 1985-01-02 Marcel Richard Medicine, especially useful in psychiatry, which uses as the active constituent a lithium N-alkylcarbamoyl phosphate

Also Published As

Publication number Publication date
FR2520364B1 (en) 1984-05-04

Similar Documents

Publication Publication Date Title
CA1305140C (en) Protected n -9-(1,3-dihydroxy-2-propoxymethyl) guanine derivatives
EP0399856B1 (en) Pteridin-4 (3H)-ones, processes for their preparation and medicaments containing them
CS226181B2 (en) Method of preparing 4-amino-5-alkylsulphonylorthoanisamide derivatives
FR2489319A1 (en) DERIVATIVES OF AMINO-4 BUTYRIC ACID AND MEDICAMENTS, PARTICULARLY ACTIVE ON THE CENTRAL NERVOUS SYSTEM, CONTAINING
CA2515384A1 (en) Medicament for inhibiting tumour growth
US4599355A (en) Treatment of sleep disorders
CH644368A5 (en) Hydroxylated pyrimidine derivatives, their preparation and therapeutic composition containing them
FR2520364A1 (en) Lithium carbamoyl phosphate(s) - are anti:aggression, sedative, and anticonvulsants
FR2532647A1 (en) ACETYLSALICYLIC ACID THIOESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
KR900006132B1 (en) Gem - dihalo - 1,8 -diamino - 4- aza - octane
EP0280603A1 (en) Absolute S confirmation enantiomers of amide derivatives of 3-aminoquinuclidine, process for their preparation and their therapeutical use
EP0129628A1 (en) Medicine, especially useful in psychiatry, which uses as the active constituent a lithium N-alkylcarbamoyl phosphate
EP0133096B1 (en) Synergistin derivatives, their preparation and pharmaceutical compositions thereof
FR2470770A1 (en) NOVEL B-IMIDAZOLYLETHYL ETHERS OF QUINOLINE-2 OR 4-METHANOLS, PARTICULARLY USEFUL AS ANTIMICROBIALS, AND PROCESS FOR THE PREPARATION THEREOF
US3711609A (en) Certain furazan derivatives in therapeutic compositions and methods
FI84817C (en) FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE GEM-6,6-DIFLUOR-1,12-DIAMINO-4,9-DIAZADODECANE.
SU1447283A3 (en) Method of producing condensed derivatives of as-triazine
DE2827805A1 (en) ALPHA VINYL AMINO ACIDS AND THE PROCESS FOR THEIR PRODUCTION
CA1068270A (en) 2,4-diamino-5-bromo-6-chloro pyrimidines, process of making them and pharmaceutical applications
US4237270A (en) Derivatives of carboxyalkyl imino- and thioxo-barbituric acids
EP0347305B1 (en) [(Aryl-4-piperazinyl-1)-2-ethoxy]-3 p cymene, the ortho-, meta-, para-monosubstituted or disubstituted phenyl ring derivatives, process for their preparation and medicaments containing the same as the active principle
LU81797A1 (en) ANTIVIRAL COMBINATIONS
CH658786A5 (en) DRUGS THAT CONTAIN ALPHA- (N-PYRROLYL) -ACIDS OR THEIR SALTS OR ESTERS.
SU507037A1 (en) Derivatives of 5- (2,4-diethylenimino) - (sym. Triazinyl-6) amino-1,3 dioxane, exhibiting antitumor activity, and method for their preparation
RU2543375C1 (en) Methyluracil derivative and organic acid complex and method for production thereof